1. Field of the Invention
The present invention relates to a fusion protein comprising therapeutic and diagnostic capacity against chronic vascular diseases, such as atherosclerosis, a nucleic acid molecule encoding said fusion protein, a pharmaceutical and diagnostic composition which comprises said fusion protein or nucleic acid molecule, a use of said fusion protein or nucleic acid molecule for the production of a pharmaceutical or diagnostic composition, a method for the diagnosis of acute or chronic vascular diseases, as well as a method for the production of said fusion protein.
2. Related Prior Art
Atherosclerosis is a highly complex active pathological process, in the center of which is an inflammatory reaction in the walls of the sanguiferous vessels of an affected individuum. The development of atherosclerosis, the so-called atherogenesis, can be subdivided into several phases.
The early phase of atherogenesis is characterized by a so-called endothelial dysfunction. A number of different risk factors such as smoking, overweight, physical inactivity, hyperlipidemia and type II diabetes as well as other so far not identified factors cause a damage of the endothelium. The permeability of the endothelium for lipoproteins and other circulating substances in the plasma is hereby increased. As a result endothelial cells are activated and increase the expression of so-called adhesion molecules on their cell surface. Among them in particular so-called selectins initially mediate a temporary contact of specific blood cells such as monocytes and T-lymphocytes with the endothelium. Another group of adhesion molecules, the so-called cellular adhesion molecules (CAMs), causes a tight attachment of these cells to the vascular wall. In particular at branchings of the vessels—the locations where atherosclerotic lesions very often develop—mechanical forces play an additional role. Increased shearing forces can reduce the production of endothelial nitrogen (NO). NO acts as a vasodilator and has anti-inflammatory properties. Furthermore, increased shearing forces result in an increased production of adhesion molecules with the above-described results.
In the further course in particular monocytes and to a lesser extent T-lymphocytes infiltrate the subintimal room. This infiltration is mediated through another group of molecules to which e.g. the chemokine monocyte chemoattractant protein 1 (MCP-1) belongs. This results in a differentiation of the monocytes into macrophages in the subintimal room.
Moreover, in the damaged endothelium an oxidation of lipoproteins of low density (LDL) occurs and as a result oxLDL is formed. oxLDL is secreted into the subintimal room where it loaded on the macrophages resulting from the monocytes. As a result of this loading with oxLDL these macrophages are transformed into so-called foam cells, the characteristic cells of the atherosclerotic plaques which contain as further components inter alia T-lymphocytes and smooth muscle cells immigrated from the media.
Such an atherosclerotic plaque deposits on the arterial walls and is covered by a stabilizing fibrous cap consisting of smooth muscle cells and extracellular matrix. The atherosclerotic plaque is now in the center of an inflammatory reaction which results in a production of different inflammation mediators such as cytokines, chemokines, proteases etc. This can result in a necrosis of tissue in which neighborhood calcium carbonates are deposited. Thereby the vascular lumen can be narrowed up to the complete closure with the result of disturbed blood flow.
If the smooth muscle cells reduce the formation of extracellular matrix and the latter is increasingly degraded by degrading enzymes, the fibrous cap is thinned out and the atherosclerotic plaque is destabilized. The plaque can dehisce whereby the thrombogenic lipid core and collagen in the vascular wall is exposed. This results in an activation of the haemostasis system which in turn results in an occluding and non-occluding thrombus formation, i.e. in the activation of the coagulation cascade, in the center of which is the so-called tissue factor (TF). The rupture of the plaque with the formation of a thrombus becomes clinically manifest as instable Angina pectoris or acute myocard infarction.
At present the atherosclerosis is normally treated by the application of lipid lowering drugs or statines, respectively. These are a group of active substances which finally inhibit the endogenic synthesis of cholesterol. Substances which belong to the statines are inter alia Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin (Mevinolin), Mevastatin (Compactin), Pravastatin and Simvastatin. These substances have influence on the lipid metabolism in different ways, e.g. by a competitive inhibition of the key enzyme of the cholesterol synthesis, the 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase, by lowering the biosynthesis of cholesterol in the liver, by amplification of the LDL receptors on the liver cell, and by modification of lipoprotein composition. Statines have a large influence on the composition of the serum lipids and cause inter alia a slight increase of the concentration of so-called “high density lipoproteins” (HDL) and a strong decrease of the LDL concentration. Finally, by the effect of the statines a fewer amount of fats circulate in the blood, so that the atherosclerotic plaques store less fat and thereby the risk of a thrombosis and the endangerings resulting therefrom decrease.
Even though a number of other positive characteristics are attributed to the statines, the latter came under criticism for a noticeable accumulation of rare, however fatal side effects on muscles and kidneys in connection with their intake. For this reason in particular the active substance Cerivastatin (e.g. Lipobay®, Zenas®) has been removed from the German market in August 2001.